	Three-dimensional printing (3DP) is also known as additive manufacturing because these technologies create a part by adding material layer by layer, guided by a 3D computer model. Various types of 3DP are being used in manufacturing in industries ranging from aerospace to medical devices, and some of the 3DP technologies are being explored for use in manufacturing of oral-solid dosage (OSD) drugs and drug-device combination products. 

spoke with Abdul Basit, professor of Pharmaceutics at the University College London (UCL) School of Pharmacy, and Alvaro Goyanes, director of Development at FabRx, which was started up in 2014 by researchers from UCL, about their 3D-printed tablets they call printlets and the different methods of 3DP that can be employed to manufacture OSD drugs. Basit is also one of the editors for a recently published book, 

What are the advantages of 3DP for drug manufacturing?

The possibility of easily creating 3D printed tablets (printlets) or medical devices just by modifying a digital file offers many opportunities. For example, by changing the object size or the infill (i.e., percentage of material inside the object), the mass of the printlet, and hence the dose of the medicine, can be flexibly altered. Conventional pharmaceutical manufacturing processes are inherently laborious, resource intensive, and dose inflexible. Indeed, there are limited commercially available dosages for certain medications, often requiring patients to split or crush their tablets to get the right dose. Instead, 3DP can enable the efficient design and preparation of small batches of medicines, comprising an individualized dose, shape, and size for each patient. In turn, this technology could reduce the risk of medication errors and side effects, while improving treatment efficacy and adherence. Due to the compact and user-friendly nature of the 3D printers, it could be possible to integrate this technology into a hospital or community pharmacy setting, enabling on-demand medicine production on the front-line. This technology is likely to be transformative in pediatric medicine, in which the dose of medicines can change rapidly, depending on the age or weight of the child. Furthermore, it is possible to combine two or more drugs into the same printlet, reducing the number of tablets that one person has to swallow, which is especially important in geriatric populations. Therefore, our aim at FabRx is to optimize the 3DP technology to enable the production of personalized medicines for each individual patient.

	We are confident that 3DP will cause a paradigm shift in the way that medicines are designed and manufactured, moving away from a ‘one-size-fits-all’ approach toward small-scale personalization. 3DP offers many opportunities to researchers by creating customized formulations that will be useful in clinical trials for testing new drugs, in the treatment of rare diseases (where the number of patients is low and costs are high), or in treatments where doses change frequently depending on therapeutic needs (e.g., narrow therapeutic index medicines). In the near future, we envision that hospitals and pharmacies will have 3D printers on-site, enabling healthcare professionals to print out tailor-made medicines on-demand. 

	The use of 3DP for customized medical devices has been widely explored for many types, including hip replacements, prosthetics, and even in dentistry. We are confident that in the future these devices will also incorporate drugs, such as antibiotics or anti-inflammatory drugs, which will help with the healing process and increase the success rate of these implanted devices. These devices can be tailored for each individual in terms of size and shape using a 3D model obtained from imaging techniques, and they can also be personalized in terms of the drug and the dose that they incorporate.

What are some of your current projects? 

We are identifying and formulating the most promising drugs for personalized medicine that could benefit from 3DP technology to be first on the market. At the same time, we are working to develop and adapt this technology for printing medicines, as well as integrate a quality control system in the printer, to enable both the production and real-time release of medicines at the dispensing point. We are also working in formulation development to ensure that the right formulations containing the right materials are produced, which can then be printed at the touch of a button. Furthermore, we are planning to conduct clinical trials and human studies to demonstrate that our technology is safe and fit-for-purpose.

	Not all 3DP technologies are suitable for medicines. We are screening which ones are suitable, testing them by printing medicines, and trying to bring them to the market as soon as possible. We need to employ technologies that can be adapted to use pharmaceutical-grade excipients and medicines and that will be safe. We also need to be able to completely control the quality of the 3D-printed medicine.

	We are focused on developing the world’s first pharmaceutical printer, because there are currently no printers adapted for these formulations. We are aiming to place the first printers within hospitals in two years, although we have started the first studies with patients in a hospital in June 2018. A critical factor centers around regulatory requirements; right now, it is not clear how the approval process will be constructed, if the printing process is going to be considered a manufacturing step (which has much higher control and regulation) or a compounding step (which is performed every day in hospitals with less strict regulation). As a company, we are scoping out which medicines could benefit the most from 3D printing and will demonstrate these formulations are safe within clinical trials, animal and human studies.  

What 3DP technologies are you considering for OSD drug manufacturing? 

We are evaluating a wide variety of 3DP technologies, in particular those that offer the best potential in developing better medicines, including selective laser sintering (SLS) and fused deposition modeling (FDM). Our novel FDM-type 3DP process involves a semisolid material being heated and extruded through a nozzle, which quickly solidifies on the build plate to create the designed printlet. 

	We are very excited by the use of SLS 3DP; the process is very simple and enables the production of printlets just by using a laser to bind a drug-powder mixture. It is not necessary to get a filament by hot-melt extrusion as in FDM technology, and depending on the materials that we select, we can get very fast or targeted release of the drug in specific regions of the gastrointestinal tract. Although SLS is more expensive than FDM technology, the costs are going down due to the development of new desktop printers.

Can you describe your stereolithography (SLA) process for drug-loaded devices? What are the pros/cons of this compared to extrusion? 

In SLA, the starting material is a resin that gets solidified by the action of a laser or light. This technology is fast; incorporation of the drug within the solution is easy; and the resolution is really high. We think that SLA could be the best approach for the manufacture of medical devices, where the resolution of the object is important (such as with stents). The main drawback of this technology is the use of excipients that are not GRAS (generally recognized as safe) approved by FDA. A lot of research is currently underway to overcome this drawback, and it is only a matter of time before the market will see new resins and polymers approved for pharmaceuticals, in the same way that they are approved for dental applications. 

	1.    American Association of Pharmaceutical Scientists, A. Basit and S. Gaisford, Eds., 

AAPS Advances in the Pharmaceutical Sciences Series 31 (Springer, 2018). 

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3D printing is being explored as a manufacturing method for on-demand, personalized medicine.

Considering 3D Printing for Solid Dosage Forms

	The global cold chain market continues to grow at a strong rate. Valued at $147.55 billion in 2017, it is expected to expand at a compound annual growth rate of 15.0% between 2018 and 2025, according to a report by Grand View Research. Insulated containers and boxes dominate the market and are projected to maintain a steady growth rate (1).

	Insulated containers and boxes play an essential role in protecting temperature-sensitive drugs from prolonged exposure to temperatures outside the range specified on their labels. Although a few insulated shippers are intended to be returned for reuse or recycling, many designs are viewed as being less than ideal from a sustainability viewpoint. Three new options combine temperature protection with an enhanced sustainability profile. 

	The ClimaCell paper-based insulator from TemperPack is designed to replace expanded polystyrene coolers, which have a limited recycling infrastructure, and is capable of protecting temperature-sensitive shipments for up to 80 hours. Certified to the standards of the Fibre Box Association and the American Forest & Paper Association, it can be recycled in the corrugated waste stream and significantly reduces packaging waste. “With the massive growth in eCommerce-fueled perishables like food and medicine, we wanted to introduce ‘guilt-free’ insulation that was just as easy to recycle as the cardboard box it came in,” said James McGoff, co-CEO of TemperPack (2).

To reinforce the recycling message, the ClimaCell insulator carries the How2Recycle mark (see 

). How2Recycle, a project of the Sustainable Packaging Coalition, promotes recycling by creating a clear, well-understood, and nationally harmonized label that tells consumers how to recycle a package. “Consumers unknowingly recycle things that aren’t recyclable and throw things out that should have ended up in their curbside recycling bins,” notes McGoff. “Getting the How2Recycle certification will help ensure that anyone who receives a ClimaCell product will know that it can be disposed of alongside the cardboard box or paper bag it came in,” he explained (3).

	ClimaCell insulation can be printed with custom graphics and messaging and is designed to maximize thermal performance and moisture resistance, while minimizing weight and storage space. “We found that companies in this space put a high value on communicating their sustainability efforts…, and we wanted to offer something that looks as good as it performs,” concluded John Briney, director of Marketing at TemperPack (2). 

	Another recyclable insulation option, TempGuard thermal insulation from Sealed Air, is made from recycled paper and tested to International Safe Transit Association certification standards to ensure it maintains required temperatures for overnight and two-day ground shipping. The material also cushions contents (4).

	OptumRx, a pharmacy-care services firm, has adopted recyclable packaging to eliminate polystyrene in the delivery of temperature-sensitive specialty and maintenance prescriptions. The packaging consists of 100% renewable cotton and is also biodegradable, compostable, and reusable. Converting to the packaging for four-million prescriptions per year is projected to save 17-million gallons of water, four-million kilowatt hours of energy, and two-million pounds of carbon dioxide emissions. “Our new packaging ensures each shipment maintains the highest standard of quality and effectiveness, while reducing the environmental footprint of our medication home delivery services,” said Jon Mahrt, chief of Operations at OptumRx (5).

	1. Grand View Research, “Cold Chain Market Size, Share & Trends Analysis Report by Packaging, by Equipment, by Type (Monitoring Components, Transportation, Storage), by Application, by Region, and Segment Forecasts, 2018 – 2025,” www.grandviewresearch.com/industry-analysis/cold-chain-market, accessed Sept. 12, 2018. 

	2. TemperPack, “TemperPack Launches ClimaCell, a Certified Recyclable Packaging Solution for Perishable Shipments,” Press Release, May 10, 2018. 

	3. TemperPack, “TemperPack Partners with How2Recycle Label Program for Its ClimaCell Product Line,” Press Release, Sept. 5, 2018. 

	4. OptumRx, “OptumRx Introduces 100% Sustainable Packaging for Medication Home Delivery,” Press Release, Aug. 16, 2018. 

	5. Sealed Air, “Sealed Air Supplies Sun Basket with Recyclable Packaging for Recipe Deliveries,” Press Release, Jan. 18, 2018. 

Insulated shippers boost recyclable and renewable content. 

Equipment and Processing Report-09-19-2018

Considering 3D Printing for Solid Dosage Forms

Cold Chain Goes Green